Hypertension is an insidious disease which affects many people. Hypertension is generally defined as an abnormally increased blood pressure. It is clinically recognized as an elevation of systolic arterial blood pressure of 150 mm Hg or greater and/or an elevation of diastolic arterial blood pressure of 90 mm Hg or higher. Certain risk factors, e.g., hypercholesterolemia, diabetes, smoking, and a familial history of vascular disease, in conjunction with hypertension may predispose individuals to arteriosclerosis and consequent cardiovascular morbidity and mortality.
During the past three decades, morbidity and mortality resulting directly or indirectly from hypertension have fallen with the development of effective pharmacological agents. Several anti-hypertensive drugs that act predominantly on the peripheral sympathetic nervous system, adrenergic receptors, autonomic ganglia, and/or on the renin-angiotensin system have been described and include, for instance, propranolol, methyldopa, clonidine, and prazosin, to name but a few. Diuretic agents have also become a mainstay in anti-hypertensive therapy, and include thiazides and closely related phthalimidine derivatives, e.g., chlorthalidone. Others, such as hydralazine, act as vasodilators by causing the direct relaxation of arteriolar vascular smooth muscle.
In general, however, drug therapy for hypertension is reserved for those individuals whose blood pressure cannot be maintained in an acceptable range by non-pharmacological means. Of the non-pharmacological treatments for hypertension, weight reduction and salt (sodium chloride) restriction have been considered to be the most successful. Restricting dietary salt, although of somewhat limited and unpredictable effect, can in some cases reduce diastolic blood pressure to an extent comparable to that achieved by treatment with some of the pharmacologic agents.
Patients whose cause of hypertension is not readily apparent are said to have "essential hypertension." This group comprises approximately 95% of the patients treated for hypertension. Patients with essential hypertension whose blood pressure decreases with restriction of dietary sodium chloride and increases with its subsequent supplementation are characterized as having "salt-sensitivity" or, more precisely, "sodium chloride-sensitive" hypertension. Fujita et al., Am. J. Med. (1980) 69:334 and Kurtz et al., N. Engl. J. Med. (1987) 317:1043. Certain elements of the population have been reported to be more salt-sensitive than others, and thus exhibit greater blood pressure changes when subjected to different dietary intakes of NaCl (see, for example, Weinberger, et al., J. Am. Coll. Nutr. 1:139-148, 1982; Luft, et al., Am. J. Med. 72:726-736, 1982; Dustan, et al., Am. J. Med. Sci. 295:378-383, 1988; and Sullivan, et al., Am. J. Med. Sci. 295:370-377, 1988.
The prevalent view is that the capacity of sodium chloride to increase blood pressure depends only on its sodium component and that, hence, all commonly ingested sodium salts have this capacity (Sodium and Potassium in Foods and Drugs: NAK Conference Proceedings, White and Crocco, eds., Amer. Med. Assn., Chicago, 1980; Willis, ed., FDA Drug Bulletin (1983) 13:25). A standard pharmacological textbook, Goodman and Gilman, The Pharmacological Basis of Therapeutics, 7th Ed., 1985, recommends that sodium restriction should be encouraged for hypertensive patients and used as a definitive therapy if effective.
Some studies have suggested that the anion component of a dietary sodium salt may determine the extent to which that sodium salt induces an increase in blood pressure. Kurtz et al., Science (1983) 222:1139; Whitescarver et al., Science (1984) 223:1430; and Kurtz et al., New Engl. J. Med., (1987), 317:1043. These studies suggest that both the sodium and chloride ions of NaCl are required for its capacity to increase blood pressure.
The results of clinical and epidemiological studies suggest that the amount of potassium in the diet may also be an important determinant of blood pressure in patients with hypertension and, in some instances, in normotensive subjects. It has been observed that increasing potassium intake by the administration of a dietary supplement of potassium tends to lower blood pressure. (Addison, et al., Can. Med. Assoc. 18:281-285, 1928; Morgan, et al., Clin. Sci. 63:407s-409s, 1982; Holly, et al., Lancet 2:1384-1387, 1981; Fujita, et al., Hypertension 6:184-192, 1984; MacGregor, et al., J. Cardiovasc. Pharmacol. 6:S244-S249, 1984, Siani et al., Br. Med. J. 294:1453-1456; and Obel, J. Cardiovasc. Pharmacol. 14:294-296, 1989). The anti-hypertensive effect of increasing potassium intake, however, has usually been small and variable.
In one experimental program, the blood pressure-lowering effect of dietary potassium supplementation was insignificant in patients on moderately restricted NaCl diets. Smith, et al., Br. Med. J. (1985) 290:110. Indeed, no anti-hypertensive effect of potassium was observed in studies by some investigators. See, Richards et al., Lancet (1984) 1:757 and Skrabal et al., Klin. Wochenschr. (1984) 62:124.
The possible use of a potassium salt other than potassium chloride, namely potassium citrate, to treat hypertension has also been suggested in the technical literature. Addison, Id. In that report, summarizing experiments on five subjects on "salt-poor diets", potassium citrate was said to exhibit a blood pressure lowering effect. Addison claimed that potassium citrate was more effective than potassium chloride in two of the three patients in whom he compared the hypotensive effect of the two potassium salts. In neither of these two instances, however, does the reported data justify the claim that potassium citrate was more effective than potassium chloride in reducing blood pressure. Indeed, to our knowledge, potassium citrate has not been recommended as a therapy for hypertension in any publication in the medical literature in the sixty years since the date of the Addison paper.
What is still urgently needed is an effective method for treating essential hypertension which utilizes a potassium compound that may be conveniently administered, preferably as a dietary supplement, which avoids concomitant administration of chloride, which is relatively easy to manufacture in bulk, and which may be made available at comparatively low cost. The present invention fulfills these and other related needs.